To date, there is no treatment to slow the progression of Parkinson's disease (PD). PD symptoms are caused by the slow degeneration of dopaminergic (DA) neurons in the ventral midbrain, which originate in the substantia nigra pars compacta (SNpc). DA neurons are characterized by specific genes necessary for dopamine production, which are regulated by orphan nuclear transcription factor Nurr1 (NR4A1). Decreased expression of Nurr1 causes loss of the dopaminergic phenotype in vivo and in vitro, thus is required for normal neurologic health and DA maintenance. Neuroinflammation triggered by glial cell activation has been proven to be a major causing factor of DA degeneration in PD. Interestingly, Nurr1 also provides a cell-specific role by constitutive suppression of neuroinflammatory gene expression in glial cells. This suggests Nurr1 could provide DA phenotypic support and neuroprotection to neurons of the SNpc if forced expression was maintained in astrocytes and neurons throughout PD progression. Nurr1 activation is also necessary for nuclear transcription, yet no endogenous ligands have been identified. However, we have demonstrated small lipophilic molecular compound, C-DIM12, to be a potent activator of Nurr1 and possess neuroprotection in a MPTP mouse model of PD. Challenges remain on genetically modifying specific cell types in the brain without off- target side effects. Yet, we hae tested specific non-pathogenic adeno-associated virus (AAV) vectors capable of transmitting a Nurr1 transgene into the SNpc and infecting both DA neurons and astrocytes. Thus, it is the Central Hypothesis of this proposal that selective overexpression of Nurr1 in DA neurons and astrocytes using AAV-based gene delivery will provide neuroprotection from MPTP-induced neurotoxicity and enhance the neuroprotective efficacy of C-DIM12 both in vitro and in vivo. The following Specific Aims will test this hypothesis: Specific Aim 1- Optimize the expression of AAV-Nurr1 in astrocytes and neurons and determine the effect of cell-specific Nurr1 expression against neurotoxic insult in vitro; Specific Aim 2- Determine the neuroprotective efficacy of cell specific AAV-Nurr1 overexpression in a mouse model of PD. Completion of these aims will increase our understanding of mechanisms by which Nurr1 regulates neuronal survival and glial activation in models of PD. Additionally, we anticipate these studies will expand our knowledge of candidate genes targeted for PD therapeutics.